An Approach to Chronic Diarrhoea 369

An Approach to 62 Chronic Diarrhoea

SHOBNA J BHATIA, PRAVEEN MATHEW

Diarrhoea is a universal human experience. It is both osmotic forces generated by the transport of solutes, i.e. a symptom and a sign. electrolytes and nutrients. Molecular pathways of ion On symptoms it is defined as abnormal passage of and nutrient transport across the mucosa have been well three or more loose or liquid stools per day. As a sign, characterized. Identification of 5 specific congenital diarrhoea is an increase in stool weight (or volume) of diarrhoeal disorders (Table 1) has confirmed the more than 200 grams (or mL) per 24 hours on a Western importance of certain ion transporter mechanisms in diet. Previous studies have suggested that stool weight health and disease. is higher in Indians, and the upper limit of normal daily Table 1: Congenital diarrhoeal disorders stool weight for Indians is thus kept at 400 g. S. No Defective transport Mutated Diarrhoea should not be defined solely in terms of mechanism gene fecal weight because fecal consistency and weight correlate best with the ratio of water-holding capacity 1. Congenital chloride Chloride bicarbonate DRA diarrhoea exchange of insoluble solids to the total water present. 2. Glucose galactose Glucose stimulated SGLT – 1 Diarrhoea is generally considered acute when it lasts malabsorption sodium absorption less than two or three weeks. Chronic diarrhoea is 3. Congenital sodium Sodium hydrogen NHE 3 defined if symptoms persist for more than four weeks. diarrhoea exchange Chronic diarrhoea is a common clinical problem. 4. Congenital acid Sodium dependent ABAT Prevalence of chronic diarrhoea in the general popula- diarrhoea bile acid Absorption tion ranges between 3-5%. WHO has stated it could be 5. Congenital lactase Lactase phlorizin LCT between 5-20%. Unlike acute diarrhoea which is mostly deficiency hydrolase self-limited, chronic diarrhoea often persists, unless some therapy is instituted. This makes an accurate Congenital Diarrhoea Disorders diagnosis central to effective management. Effect of chronic diarrhoea on quality of life and health care Diarrhoea is often classified pathophysiologically as expenses are considerable. osmotic or secretory. Understanding Diarrhoea Osmotic diarrhoea is due to presence of poorly absorbed cations and anions (, sulfate, Diarrhoea is usually due to an excess of stool water phosphate), or poorly absorbed sugar or sugar alcohols rather than a decrease in water holding capacity of fecal (mannitol, sorbitol, ) in bowel in excess, as these solids, implying an abnormality in water transport are poorly absorbed or transport mechanisms are within the gut. Diarrhoea results when there is a saturated at low intra-luminal ion concentration, leading reduction of water absorption by as little as 1% by small to water retention. Lactose intolerance, due to lactase or large bowel. Water itself is not actively transported deficiency, is the most common clinical syndrome which but moves across the intestinal mucosa secondary to results in osmotic diarrhoea. 370 Medicine Update

Osmotic diarrhoea typically disappears with fasting by qualitative testing with Sudan stain or by quantitative or cessation of ingestion of the offending substance. Also analysis of a timed stool collection for fat. Inflammatory as electrolyte absorption is not impaired, the electrolyte diarrhoea typically contains blood or pus; these concentrations in stool water may be quite low. characteristics may be detected by a fecal blood test or, Secretory diarrhoea has many causes, it is either due staining for neutrophils in stool or lactoferrin, a to net secretion of chloride or bicarbonate, or inhibition neutrophil-derived protein. of net sodium absorption. The stimulus for secretion may come from the lumen (enterotoxins), the subepithelial Differential Diagnosis of Chronic Diarrhoea by Stool space or systemic circulation (vasoactive intestinal Characteristics peptide, , , inflammatory cytokines). I. Watery Diarrhoea Secretory diarrhoea may also result from absence of a specific absorptive pathway (congenital chlori- a. Osmotic diarrhoea—osmotic (Mg, diarrhoea), significant loss of surface area (extensive Phosphates, Sulfates) small bowel mucosal disease, as in celiac disease, Carbohydrate malabsorption inflammatory bowel disease, resective surgery etc), b. Secretory diarrhoea abnormal motility (diabetes mellitus, post-vagotomy diarrhoea) where the contact time between luminal Congenital syndromes (Congenital chloridarrhea) contents and epithelium is insufficient. Bacterial toxins Since there is a secreto/absorptive defect in secretory Bile acid malabsorption. diarrhoea, the stool electrolyte concentration is high and Inflammatory bowel disease (Crohn’s disease, the diarrhoea persists on fasting. microscopic colitis) The classification of diarrhoea as secretory or osmotic Drugs (most antibiotics, anti-neoplastic, antiarry- is helpful; pure secretory or pure osmotic diarrhoeas are thmics, theophylline) uncommon. Most clinically significant diarrhoeas are abuse complex, rather than being produced by a single pathophysiological mechanism. Disordered motility/regulation (postvagotomy, post-sympathetectomy, diabetic autonomic neuropathy, Recently a new variety of diarrhoea has been irritable bowel syndrome) described due to mutant neurogenin – 3, a transcriptor factor pivotal to development of pancreatic beta cell. Endocrine diarrhoea (hyperthyroidism, Addison’s Features of this disorder are that, diarrhoea ceases in disease, , VIPoma, pheochromocytoma). the fasting state, is induced when anything other than Other tumors (Colon cancer, lymphoma) water is ingested, mucosa of small intestine is normal, Idiopathic secretory diarrhoea. except for absence of and there is no inflammatory component. The exact mechanism still II. Inflammatory Diarrhoea remains unclear. Inflammatory bowel disease (ulcerative colitis, Differential Diagnosis of Chronic Diarrhoea Crohn’s disease, ulcerative jejunocolitis) Clue to the site of diarrhoea can be obtained on the Infections (pseudomembranous colitis, invasive basis of volume of individual stools. When left side of bacterial infection like TB and Yersiniosis, ulcerating colon, including the rectosigmoid, is involved the stools viral infection like CMV and Herpes simplex, invasive are frequent, small in quantity, and may be painful. If parasitic infections like amebiasis) the source of diarrhoea is upstream in right colon or Ischemic colitis small bowel stools are large volume, and less frequent. Radiation colitis Another schema for classifying diarrhoea is based Neoplasia (colon cancer, lymphoma). on characteristic of stool produced—watery, fatty and inflammatory. III. Fatty Diarrhoea Watery stools are typically runny and lack pus, blood Malabsorption syndromes or fat. Watery diarrhoea is subdivided into secretory or osmotic depending on stool electrolyte concentration. Mucosal disease (Celiac disease, Whipple’s disease) Fatty stools have an excess of fat, which can be shown Short bowel syndrome An Approach to Chronic Diarrhoea 371

Small bowel bacterial overgrowth flatulence suggests increased fermentation of carbo- Mesenteric ischemia. hydrates by colonic bacteria, caused by ingestion of poorly absorbed carbohydrate or malabsorption of Maldigestion carbohydrate by small intestine. Pancreatic exocrine insufficiency Other coexisting symptoms such as abdominal pain, Inadequate luminal bile acid concentration. bloating, fever and weight loss should be enquired. There should be a thorough enquiry of drugs, previous Epidemiology of Chronic Diarrhoea in India surgery, radiation therapy, nutritional remedies, herbal Chronic diarrhoea is a common problem in India. medicines etc. Diet should be reviewed for ingestion of Most studies in India have classified the diarrhoea large quantities of poorly absorbable carbohydrates in depending on site of involvement—small bowel and fruit juices, soda pop, sugar-free candies, chewing gum large bowel diarrhoea. In studies from south India in etc. 1970s, tropical sprue was the commonest cause of History is essential to differentiate patients with chronic diarrhoea. It is now believed that frequency of functional bowel disorders, like irritable bowel TS is decreasing, possibly due to an improvement in syndrome (IBS) which may be suggested by abdominal standard of living, as also more frequent use of pain with defecation, long history usually dating to antibiotics. adolescence or young adulthood, excess , exacer- In a recent study at a tertiary hospital in north India bations with stress etc. Factors against the diagnosis of on malabsorption, the causes were tropical sprue (39%), IBS are recent onset symptoms, older age group, Crohn’s disease (9%), celiac disease (9%), giardiasis (8%), nocturnal diarrhoea, weight loss, blood in stool and stool primary small intestinal bacterial overgrowth syndrome weight > 400 g/day. (6%), intestinal tuberculosis (4%), AIDS (2%), amyloi- dosis (2%), intestinal lymphangiectasiasis (1%), Examining the Patient panhypogammaglobulinemia (2%). Under representa- Physical examination may provide more direct tion of tuberculosis in the study was possibly because evidence of cause of diarrhoea. Characteristic skin chan- empirical treatment with anti-tubercular medicines was ges may be seen in celiac sprue (dermatitis herpiti- a common practice among community physicians. formis), Addison’s disease (heightened pigmentation), Celiac disease was considered rare in India, it is being amyloidosis (waxy papules, pinch purpura), carcinoid described frequently now, especially from northern syndrome (flushing), glucagonoma (migratory India. The prevalence in school children in Punjab is one necrotizing erythema). Peripheral neuropathy and in 310. orthostasis may give clue to amyloidosis/diabetic The causes of large bowel diarrhoea in India are autonomic neuropathy. Thyroid nodule with cervical ulcerative colitis (25%), microscopic colitis (7%), adenopathty may suggest medullary carcinoma. colorectal malignancies (4%), intestinal polyps (4%) and Lymphadenopathy may suggest lymphoma, tuber- irritable bowel syndrome (45%). culosis or HIV infection. Arthritis may be noted in inflammatory bowel disease, Whipple’s disease and Speaking to the Patient some enteric infections. Tremors and other signs of hyperthyroidism may be present. A careful medical history is key to the evaluation of chronic diarrhoea. Stool frequency is the easiest Preliminary Evaluation of Chronic Diarrhoea characteristic for patients to define. Patients have poor notion of stool volume; watery stools suggest an osmotic Analysis of stool sample can be used to categorize or secretory process. Physician should ask about the diarrhoea and thereby limit the number of conditions relationship to meals or fasting, as continuation of to be considered in differential diagnosis. Stool analysis diarrhoea during fasting is one of the criteria for can be timed (i.e. 24-48 hour stool sample) where stool secretory diarrhoea. Presence of blood or pus in stools weight, output of various components such as fat, signals possibility of malignancy or inflammatory bowel electrolytes can be measured accurately. Random stool disease, although blood is frequently due to hemorrhoids sample can still provide clues when evaluated for in patients with frequent evacuations. Presence of oil sodium, potassium, pH, testing for occult blood, droplets or food particles in stools is suggestive of searching for WBCs or determining surrogate marker malabsorption, maldigestion or intestinal hurry. Excess for WBC i.e., fecal lactoferrin. It is important to send 372 Medicine Update multiple samples if parasitic infestation like strongy- Sigmoidoscopy/colonoscopy is used to visualize and loidosis or giardiasis is suspected. take biopsy of colonic mucosa as in melanosis coli, Stool osmotic gap is calculated by subtracting twice tuberculosis, tumors, Crohn’s disease, ulcerative colitis the sum of sodium and potassium from 290 mOsm/kg, and amebiasis. Conditions where the colonic mucosa the osmolality of stool within the body. The osmotic gap appear normal endoscopically, but which can be is small (< 50 mOsm/kg) in secretory diarrhoea and a diagnosed histological include microscopic colitis, large osmotic gap (100 mOsm/kg) is seen in usually due amyloidosis, Whipple’s disease, granulomatous to Osmotic diarrhoea. If pH of stool is acidic < 6 it is infections and schistosomiasis. supportive of carbohydrate malabsorption. Testing for peptide secretory tumors like carcinoid, Zollinger Ellison syndrome, mastocytosis should be Occult blood and fecal leucocytes are seen in based on pretest probability depending on clinical and inflammatory diarrhoeas. radiographic /endoscopic possibility and not as a Stool fat concentration can be measured quanti- screening tests. tatively, by chemical means on a timed (48-72 hr) Endocrine tests like a fasting blood sugar in collection. Steatorrhea is defined as excessive loss of fat suspected diabetics, TSH in hyperthyroidism, ACTH in the stool > 7 g or 9% of fat intake for 24 hours. For a stimulation tests in patients with clinical suggestion of valid study patients should consume 70 to 100 g of fat Addison’s disease should be asked for. per day for three days before and during the timed collection. When a random sample is available semi- In spite of all investigation 25% of all cases of secretory diarrhoeas the cause remains unidentified and quantitative estimation of fat excretion by means of a they are labeled as idiopathic secretory diarrhoeas. Sudan stain of fecal smear is helpful, if fat excretion is more than 14 g/day. Osmotic diarrhoea—It has limited differential diag- nosis, usually due to ingestion of exogenous magnesium, Evaluation of Chronic Watery Diarrhoea consumption of poorly absorbed carbohydrates or carbohydrate malabsorption. Magnesium can be Secretory diarrhoea—has a broad differential measured in stools by atomic spectrophotometry. diagnosis. Infections should be ruled out by stool Excretion of more than 30 mEq of magnesium daily or cultures and special tests for other organisms. HIV status concentration in stool water of more than 90 mEq/L should be clarified. Some organisms like Aeromonas, strongly suggest magnesium-induced diarrhoea. This plesiomonas, coccidia, microsporida, etc. require special may be intentional ingestion/accidental ingestion/ microbiological techniques like PCR. Giardia and therapeutic content in antacids or mineral supplements. strongyloidosis can be detected by distal duodenal Low fecal pH is usually due to ingestion of poorly mucosal biopsy examination. Small bowel bacterial absorbed carbohydrates or carbohydrate malabsorption. overgrowth which can cause secretory diarrhoea by Isolated carbohydrate malabsorption is seen in lactase toxins can be screened by glucose breath hydrogen test. deficiency. Poorly absorbed sugar alcohols are used as But the standard test is to document >106 bacteria by artificial sweeteners, sorbitol or mannitol. Excess quantitative culture of a small bowel aspirate. fructose is also not absorbed. These patients complain Structural diseases such as short bowel syndrome, of gas and bloating sensation. Breath hydrogen with gastrocolic or enterocolic fistula, mucosal disease, lactose as sugar can confirm the diagnosis of carbo- inflammatory bowel disease and tumors including hydrate malabsorption. Once a specific diagnosis has lymphoma should be sought by radiographic and been proposed for osmotic diarrhoea therapeutic trial endoscopic techniques. Small bowel series/radiographs of an elimination diet can confirm the diagnosis. are helpful for small bowel structural diseases. CT scan helps in visualizing not only bowels, but also extrinsic Evaluation of Chronic Inflammatory Diarrhoea problems like pancreatic diseases. Chronic diarrhoea patients with white blood cells or Small bowel mucosa visualization by endoscopy or blood in stool are classified as inflammatory diarrhoea enteroscopy can be used to take biopsy and detection in usually due to mucosal disruption and inflammation. Crohn’s disease, giardiasis, celiac sprue, intestinal Diagnostic considerations include inflammatory bowel lymphoma, eosinophilic gastroenteritis, tropical sprue, disease, infections, pseudomembranous enterocolitis, Whipple’s disease, lymphangiectasia, abetalipoprotei- ischemic/radiation enteritis and neoplasia. Mucosal nemia, amyloidosis, mastocytosis and various infectious examination and biopsy must be taken for making diseases. correct pathological diagnosis. An Approach to Chronic Diarrhoea 373

Infections causing chronic inflammatory diarrhoea history of ileal resections, known enterocolic fistula. are Clostridium difficle, cytomegalovirus, tuberculosis and Supplementation of diet with exogenous bile acids amebiasis should be excluded by appropriate biopsies, should reduce steatorrhea, if bile acid deficiency is the cultures and serological tests. problem.

Evaluation of Chronic Fatty Diarrhoea CONCLUSION Evaluation is designed to distinguish between mal- Chronic diarrhoea is a challenging condition to (inadequate luminal breakdown of triglyce- evaluate and treat. By approaching each case rides) and malabsorption (inadequate mucosal transport individually, rationally directed by a careful history and of products of digestion). Fecal fat concentration physical examination, with simple triage tests, a long provides a clue to the cause of steatorrhea. Mucosal list of differential diagnosis can be made more disease is often associated with poor fluid and electrolyte manageable and appropriate treatment can be ordered. absorption, and stool fat content is diluted by unabsorbed water. In addition, triglycerides are broken SUGGESTED READING down to fatty acids in small intestine and pass into colon where they further inhibit water absorption. Mal- 1. Binder HJ. Causes of chronic diarrhoea. NEJM 2006;3553;236- digestion due to pancreatic and biliary problems 9. typically does not produce fatty acids and does not 2. Garg PK, Singh J, Dhali GK, Mathur M, Sharma MP. inhibit water absorption; this unabsorbed fat is dispersed Microscopic colitis is a cause of large bowel diarrhoea in in a smaller stool volume. Fecal fat contents greater than Northern India. J Clin Gastroenterol 1996;22:11-5. 9.5 g per 100 g strongly suggest pancreatic or biliary 3. Ranjan P, Ghosal U C, Aggarwal R, Pandey R, Misra A, Naik steatorrhea. S, et al. Etiological spectrum of sporadic malabsorption In evaluation of cause first step is to look for syndrome in northern Indian adults at a tertiary hospital. Indian J Gastroenterol 2004;23:95. structural problems of small bowel which may include 4. Sachdev A, Srinivasan V, Maheswary S, Mohan H, Ashish B, small bowel radiograph/CT scan and small bowel Singh LS. Adult onset celiac disease in north India. Trop biopsy. CT scan of the pancreas is diagnostic in most Gastroenterol 2002;23:117-9. cases of chronic pancreatitis which are associated with 5. Schiller LR, Sellin JH. Diarrhoea. In: Feldman M, Freidman steatorrhea. LS, Brandt LJ (Eds): Sleisenger and Fordtran’s Gastrointestinal If no structural problems are found then pancreatic and Liver Disease: Pathophysiology, Diagnosis and Management, 8th edition, Philadelphia Saunders, 2006. exocrine function should be evaluated. The test, bentiromide test, fecal elastase, direct measurement of 6. Schiller LR. Chronic Diarrhoea. Gastroenterology 2004;127:287- 93. fecal chymotrypsin etc are tests available, but done only 7. Sood A, Midha V, Sood N, Avasthi G, Sehgal A. Prevalence of in research laboratories. But the best test for pancreatic celiac disease among school children in Punjab, north India. J exocrine insufficiency may be a therapeutic trial of Gastroenterol Hepatol 2006;21:1622-5. pancreatic enzyme preparation with objective 8. Thomas PD, Forbes A, Green J, Howdle P, Long R, Playford R, assessment. Possibility of inadequate bile salt, or et al. Guidelines for investigation of chronic diarrhoea, 2nd solubilization of dietary fat can usually be inferred from edition. Gut 2003;52(suppl v); v1-v15.